Synthesis, biological evaluation, and docking studies of gigantol analogs as calmodulin inhibitors

Several analogs of gigantol (1) were synthesized to evaluate their effect on the complexes Ca2+–calmodulin (CaM) and Ca2+–CaM–CaM sensitive phosphodiesterase 1 (PDE1). The compounds belong to four structural groups including, 1,2-diphenylethanes (2–11), diphenylmethanes (13–15), 1,3-diphenylpropenones (16–18), and 1,3-diphenylpropanes (20–22). In vitro enzymatic studies showed that all compounds except 11 inhibited the complex Ca2+–CaM–PDE1 with IC50 values ranging from 9 to 146 μM. On the other hand, all analogs but 11, 12 and 15 quenched the extrinsic fluorescence of the CaM biosensor hCaM–M124C–mBBr to different extent, then revealing different affinities to CaM; their affinity constants (Km) values were in the range of 3–80 μM. Molecular modeling studies indicated that all these compounds bound to CaM at the same site that the classical inhibitors trifluoperazine (TFP) and chlorpromazine (CPZ). Some of these analogs could be worthy candidates for developing new anti-tumor, local anesthetics, antidepressants, antipsychotic, or smooth muscle relaxant drugs, with anti-CaM properties due to their good affinity to CaM and the straightforwardness of their synthesis. In addition they could be valuable tools for the study of Ca2+–CaM functions.

Some synthetic 1,2-diphenylethanes, diphenylmethanes, 1,3-diphenylpropenones, and 1,3-diphenylpropanes inhibited Ca2+–CaM–PDE1 complex and quenched the fluorescence of hCaM–M124C–mBBr.Figure optionsDownload as PowerPoint slideHighlights
► A few synthetic 1,2-diphenylethanes, diphenylmethanes, 1,3-diphenylpropenones, 1,3-diphenylpropanes inhibit Ca2+–CaM–PDE1 complex and quenched the fluorescence of hCaM–M124C–mBBr.
► Molecular modeling revealed that these compounds bound to CaM at the same site that trifluoperazine (TFP) and chlorpromazine (CPZ).
► Some of these analogs could be worthy candidates for developing new drugs, with anti-CaM properties due to their good affinity to CaM and the straightforwardness of their synthesis.